CN110283104B - Preparation method of arginine perindopril - Google Patents
Preparation method of arginine perindopril Download PDFInfo
- Publication number
- CN110283104B CN110283104B CN201810957411.8A CN201810957411A CN110283104B CN 110283104 B CN110283104 B CN 110283104B CN 201810957411 A CN201810957411 A CN 201810957411A CN 110283104 B CN110283104 B CN 110283104B
- Authority
- CN
- China
- Prior art keywords
- perindopril
- arginine
- preparation
- salt
- tert
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of medicine synthesis, and relates to a preparation method of arginine perindopril. The preparation method of arginine perindopril is characterized in that organic amine salt of perindopril is reacted with L-arginine to obtain arginine perindopril. The arginine perindopril prepared by the method has white powder, the purity of the arginine perindopril can reach more than 99.9 percent, the yield of the arginine perindopril is more than 80 percent, the technical process is easy to pump and filter, and the phenomenon of agglomeration is avoided.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of arginine perindopril.
Background
Arginine perindopril is a medicine for treating mild and moderate essential hypertension, which is introduced by Schweiya, France, and compared with tert-butylamine perindopril, the compound is more stable, the shelf life can be prolonged to more than 2 years, and arginine perindopril and amlodipine besylate can form a compound preparation which has outstanding curative effect when being used for treating adult patients with hypertension which can not be fully controlled by single medicine.
CN101389603 relates to a preparation method of an alpha crystal form, which adopts DMSO, water, and methylcyclohexane as solvents to prepare a hydrate; CN101389604 relates to a process for the preparation of crystalline form beta, which comprises refluxing arginine perindopril alpha crystalline form with toluene or acetonitrile at high temperature to prepare anhydrous form beta crystalline form.
The above publications all require the use of perindopril as raw material for the reaction with arginine, and the poor stability of perindopril is difficult to prepare and purify, and the post-treatment properties of arginine perindopril according to the above publications are not ideal and not easy to be industrially operated, so that the development of a more suitable process for preparing arginine perindopril is needed
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the method which has the advantages of simple process, convenient operation, low production cost, high product purity and stable process and is suitable for industrial production of the arginine perindopril.
The invention relates to a preparation method of high-purity arginine perindopril, which comprises the following steps: an organic amine salt of perindopril is reacted with L-arginine to obtain arginine perindopril.
Further comprising:
(1) dissolving organic amine salt of perindopril and L-arginine in water;
(2) under the vacuum negative pressure condition, adding dimethyl sulfoxide into the solution obtained in the step (1) and then heating;
(3) adding an organic solvent into the mixed solution obtained in the step (2), and cooling and crystallizing;
(4) leaching the solid obtained in the step (3) with an organic solvent, and then carrying out vacuum drying;
(5) stirring the solid obtained in the step (4) and then carrying out suction filtration;
(6) and (5) drying the obtained product in vacuum to obtain the arginine perindopril.
The organic solvent may be a mixture of at least one of,
further, the mole ratio of the organic amine salt of perindopril to the L-arginine in the step (1) is 1.0: 0.8 to 1.05.
Further, the vacuum negative pressure condition in the step (2) is that the vacuum negative pressure is not higher than-0.07 Mpa, and the duration is not lower than one hour.
Further, the crystallization temperature in the step (3) is 0-25 ℃.
Further, the vacuum drying temperature in the step (4) is controlled to be 40-50 ℃.
Further, the organic solvent in step (3) and step (4) is selected from: ethyl acetate, isopropyl acetate, isobutyl acetate, methyl tert-butyl ether, preferably ethyl acetate.
Further, the organic amine salt of perindopril according to the present invention is selected from the group consisting of tert-butylamine salt of perindopril, isopropylamine salt of perindopril, isobutylamine salt of perindopril, sec-butylamine salt of perindopril, diethylamine salt of perindopril, preferably tert-butylamine salt of perindopril.
The invention has the beneficial effects that: firstly, the arginine perindopril is difficult to purify, and if perindopril and arginine are used for reaction to form salt, the degradation of perindopril in the whole process needs to be controlled; secondly, it is difficult to obtain the compound in an oily or highly pure form. Extraction of perindopril by the acid hydrolysis of tert-butylamine perindopril does not readily allow the preparation of high purity and high yield perindopril and this process tends to result in excessive acid reaction with arginine; the invention directly uses tert-butylamine perindopril to be converted into arginine perindopril, and the tert-butylamine perindopril is a solid compound, so that the compound can be conveniently obtained or has high purity, the process is simple, the degradation of the compound is avoided, a part of tert-butylamine is pumped out by a negative pressure method, the forward reaction is ensured, and the product yield is improved.
Detailed Description
Example 1
Adding 70.0g of tert-butylamine perindopril, 26.2g (0.95eq) of L-arginine and 210g of purified water into a 2L reaction bottle, stirring until a reaction solution is clear, adding 770g of dimethyl sulfoxide, heating to 40-50 ℃ for reaction, keeping negative pressure below-0.07 Mpa for reaction for one hour, adding 273g of ethyl acetate after the reaction is finished, cooling to 5-25 ℃ for crystallization for 4 hours, carrying out suction filtration on the obtained solid, leaching the solid with ethyl acetate, placing the solid in vacuum drying, stirring and washing the obtained solid with ethyl acetate for 2 times, carrying out suction filtration, and finally carrying out vacuum drying for 4 hours. The yield was 82.3% and the purity was 99.96%.
Example 2
Adding 100g of isopropyl amine perindopril and 220g of L-arginine 39.4g (1eq) of purified water into a 5L reaction bottle, stirring until a reaction solution is clear, adding 660g of dimethyl sulfoxide, heating to 40-50 ℃, keeping the negative pressure below-0.07 Mpa for reaction for one hour, adding methyl tert-butyl ether after the reaction is finished, cooling to 0-10 ℃, crystallizing for 6 hours, carrying out suction filtration on the obtained solid, leaching the solid with methyl tert-butyl ether, placing in vacuum for drying, stirring and washing the obtained solid with methyl tert-butyl ether for 2 times, carrying out suction filtration, and finally carrying out vacuum drying for 6 hours, wherein the yield is 87.5 percent, and the purity is 99.94 percent.
Example 3
Adding 50g of diethylamine perindopril and 17.8g (0.9eq) of L-arginine (75 g) into a 2L reaction bottle, stirring until a reaction solution is clear, adding 350g of dimethyl sulfoxide, adding isopropyl acetate, cooling to 0-10 ℃, crystallizing for 12h, performing suction filtration to obtain a solid, leaching the solid with isopropyl acetate, performing vacuum drying, performing suction filtration to obtain a solid, performing stirring washing for 2 times with isopropyl acetate, and performing suction filtration to obtain a product after vacuum drying for 6h, wherein the yield is 83.3%, and the purity is 99.92%.
Claims (8)
1. A process for the preparation of arginine perindopril, which is characterized in that:
(1) dissolving organic amine salt of perindopril and L-arginine in water;
(2) under the vacuum negative pressure condition, adding dimethyl sulfoxide into the solution obtained in the step (1) and then heating;
(3) adding an organic solvent into the mixed solution obtained in the step (2), and cooling and crystallizing;
(4) leaching the solid obtained in the step (3) with an organic solvent, and then carrying out vacuum drying;
(5) stirring and filtering the solid obtained in the step (4);
(6) vacuum drying the obtained in the step (5) to obtain arginine perindopril;
the organic solvent in the step (3) and the step (4) is selected from one of ethyl acetate, isopropyl acetate, isobutyl acetate and methyl tert-butyl ether.
2. Process for the preparation of arginine perindopril according to claim 1, characterized in that: in the step (1), the molar ratio of the organic amine salt of perindopril to the L-arginine is 1.0: 0.8 to 1.05.
3. Process for the preparation of arginine perindopril according to claim 1, characterized in that: in the step (2), the vacuum negative pressure is not higher than-0.07 Mpa, and the duration is not lower than one hour.
4. Process for the preparation of arginine perindopril according to claim 1, characterized in that: the crystallization temperature in the step (3) is 0-25 ℃.
5. Process for the preparation of arginine perindopril according to claim 1, characterized in that: in the step (4), the vacuum drying temperature is controlled to be 40-50 ℃.
6. Process for the preparation of arginine perindopril according to claim 1, characterized in that: and (4) the organic solvent in the steps (3) and (4) is ethyl acetate.
7. A process for the preparation of arginine perindopril according to any one of claims 1 to 6, characterized in that: the organic amine salt of perindopril is selected from the group consisting of tert-butylamine salt of perindopril, isopropylamine salt of perindopril, isobutylamine salt of perindopril, sec-butylamine salt of perindopril, and diethylamine salt of perindopril.
8. Process for the preparation of arginine perindopril according to claim 7, characterized in that: the organic amine salt of perindopril is tert-butylamine salt of perindopril.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810957411.8A CN110283104B (en) | 2018-08-22 | 2018-08-22 | Preparation method of arginine perindopril |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810957411.8A CN110283104B (en) | 2018-08-22 | 2018-08-22 | Preparation method of arginine perindopril |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110283104A CN110283104A (en) | 2019-09-27 |
| CN110283104B true CN110283104B (en) | 2022-06-14 |
Family
ID=68001120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810957411.8A Active CN110283104B (en) | 2018-08-22 | 2018-08-22 | Preparation method of arginine perindopril |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110283104B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047999B (en) * | 2020-09-18 | 2022-12-02 | 天津力生制药股份有限公司 | Preparation method of gamma-crystal form arginine perindopril salt |
| SI26268A (en) | 2021-11-18 | 2023-05-31 | Zupet Rok | Procedure for the preparation of the hydrated form of perindopril L-arginine |
| CN114149357A (en) * | 2021-12-29 | 2022-03-08 | 江苏嘉逸医药有限公司 | Preparation method of gamma-crystal form perindopril arginine salt |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193863A (en) * | 2012-01-05 | 2013-07-10 | 瑟维尔实验室 | Process for the preparation of perindopril L-arginine salt |
| CN103193864A (en) * | 2012-01-05 | 2013-07-10 | 瑟维尔实验室 | Delta crystalline form of the arginine salt of perindopril, a process for its preparation, and pharmaceutical compositions containing it |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2009212902A1 (en) * | 2008-09-03 | 2010-03-18 | Apotex Pharmachem Inc. | Amorphous form of an L-arginine salt of perindopril and processes of preparation thereof |
-
2018
- 2018-08-22 CN CN201810957411.8A patent/CN110283104B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193863A (en) * | 2012-01-05 | 2013-07-10 | 瑟维尔实验室 | Process for the preparation of perindopril L-arginine salt |
| CN103193864A (en) * | 2012-01-05 | 2013-07-10 | 瑟维尔实验室 | Delta crystalline form of the arginine salt of perindopril, a process for its preparation, and pharmaceutical compositions containing it |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110283104A (en) | 2019-09-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110283104B (en) | Preparation method of arginine perindopril | |
| WO2023071293A1 (en) | Method for preparing molnupiravir | |
| CN110642738A (en) | Preparation method of lidocaine hydrochloride | |
| CN105541906B (en) | A kind of purification process of glufosinate-ammonium | |
| CN109678744B (en) | Method for continuously preparing glycine | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN104262397A (en) | Preparation method of high-purity tenofovir | |
| CN112552167B (en) | Preparation method of calcium gluconate | |
| CN108003077B (en) | Preparation and purification method of amino acid compound | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| CN113185459A (en) | Hydroxychloroquine sulfate and preparation method thereof | |
| CN108017561B (en) | Method for refining carglutamic acid | |
| CN104263795A (en) | Method for preparing chiral alpha-naphthenic glycine | |
| CN110872251A (en) | N-ethylpyridine methylamine trifluoroacetate and crystal, preparation process and application thereof | |
| CN113874351B (en) | Synthesis method of florfenicol | |
| CN111100026A (en) | Preparation method of taxol oxazole ring side chain intermediate | |
| KR100957725B1 (en) | Method for preparing intermediate of cilastatin | |
| WO2020075082A1 (en) | Process for the synthesis of carglumic acid | |
| CN104910209A (en) | Tenofovir preparation method | |
| JP2020040894A (en) | Method of purifying pregabalin | |
| CN110407735B (en) | Synthesis process of 3,4,5, 6-tetrafluoro-N-methylphthalimide | |
| CN109694389A (en) | A kind of preparation method of fosfomycin sodium | |
| CN113929632B (en) | Acipimox calcium salt and preparation method thereof | |
| CN110922345B (en) | Synthesis method of fudosteine | |
| CN108530516B (en) | Synthesis and purification process of pidotimod with high chiral purity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |